Hydrophobic Gating in Membrane Nanopores: Water at the Nanoscale

Lead Research Organisation: University of Oxford
Department Name: Biochemistry

Abstract

The properties of water play a key role in biology, underlying all aspects of cellular structure and function. All cells are surrounded by lipidic membranes, in which there exist pore-like proteins which allow communication and exchange between the inside and outside of cells. Such nanoscale pores ('nanopores') are of great importance both in cell biophysics and as potential components of novel biosensors. Nanopores are filled with water. However, water behaves differently on the nanoscale, inside pores whose diameter is 10 millionths of diameter that of a human hair. In particular, nanopores can undergo spontaneous de-wetting if their lining is sufficiently hydrophobic (i.e. 'oily'). This provides a possible way in which to control the activity of nanopores if we can control their wetting/de-wetting.

We consequently need to understand and be able to model the physicochemical basis of wetting and de-wetting at a level of accuracy good enough for predictions to aid design of novel nanopores. This can be achieved by computer simulations - combining advanced algorithms and the power of modern supercomputers.
In this way, we will determine the behaviour of water in nanopores, understanding how they can be functionally 'opened and closed' by wetting and de-wetting, and how the imposition of a voltage difference across a nanopore-containing membrane can cause the nanopores to electrowet, thereby switching them from an inactive (closed) to an active (open) state.

This fundamental research will allow us to design controllable opening/closing of new nanopores for use in biosensors and other healthcare related applications.

Planned Impact

The impact of this work will be at the synthetic biology/nanotech interface, by enabling design of novel nanopores.
Thus, whilst this study is focussed on basic biological physics, this area of research underpins technologies for biosensing in relation to healthcare.

The long-term socio-economic benefits of the project will arise principally from advances in our exploitation of biomimetic nanopores in biosensors. There will also be impact in terms of improved methods for treating water in computational drug design; and modelling of water/biopolymer interactions for 'soft' hybrid materials. The principal beneficiaries will therefore be the biotech, healthcare and pharmaceutical industries and their stakeholders.

I will ensure maximum impact and exposure of the basic science discoveries via my ongoing engagement with relevant biotech and healthcare related industries. In this respect, I note that I have had recent collaborations with biotech (an iCASE student with ONT), and pharma (iCASE studentships with UCB), as well as emerging collaborations with Ipsen and with Novo Nordisk. I am a potential project supervisor for the joint EPSRC/BBSRC Synthetic Biology CDT, and also a director of the BBSRC-funded Interdisciplinary Bioscience DTP, which runs a highly successful Industry Day to foster contacts and collaborations with industrial partners. I will continue to showcase my group's work at these events.

Publications

10 25 50
 
Description 1. Water behaviour within a nanopore/channel hydrophobic gate has been characterised for different water models
2. We have three publications which will emerge in the next 12 months in this area demonstrating its application to model peptide nanopores and to ion channel proteins
3. We have published a major review in Chemical Reviews and three primary research publications (2 in ACS Nano and 1 in J Chem Phys).
4. Studies comparing MD and QM calculations on water in nanopores continue and we hope to publish the results later this year/early next.
Exploitation Route The methods we have developed can be applied in (i) analysis of biological ion channels and (ii) modelling and design of novel biomimetic nanopores, as has been demonstrated e.g. in our published collaborative studies.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description These finding formed the basis of collaborative discussions with colleagues from IBM research (UK), and with colleagues from Spain (Santiago & Madrid). The latter two collaborations progressed via papers which have now been published. The IBM collaboration has resulted in a partnership in graduate training (a DTC in computational discovery; https://www.ox.ac.uk/admissions/graduate/courses/dphil-computational-discovery) between Oxford and IBM, and is ongoing involving a number of colleagues from both physical and biological science departments in Oxford.
First Year Of Impact 2019
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Collaboration with Dr Rebeca Garcia-Fandino 
Organisation University of Santiago de Compostela
Country Spain 
Sector Academic/University 
PI Contribution we provided advice on setup and analysis of water simulations for cyclic peptide nanopores
Collaborator Contribution a student visited my research group for 2 months to learn our simulation methods
Impact A paper has been published in ACS Nano
Start Year 2018
 
Description Oxford/IBM 
Organisation IBM
Department IBM Research in the UK
Country United Kingdom 
Sector Private 
PI Contribution We have established a major ongoing collaboration in biomolecular simulations and computational discovery between the Biochemistry Dept. and IBM Research UK.
Collaborator Contribution EPSRC iCASE studentships expertise in advanced computing methods for application to biomolecular simulations
Impact The major outcome to date is a joint DTC - see URL above
Start Year 2017
 
Description Oxford/IBM 
Organisation IBM
Department IBM Research in the UK
Country United Kingdom 
Sector Private 
PI Contribution We have established a major ongoing collaboration in biomolecular simulations and computational discovery between the Biochemistry Dept. and IBM Research UK.
Collaborator Contribution EPSRC iCASE studentships expertise in advanced computing methods for application to biomolecular simulations
Impact The major outcome to date is a joint DTC - see URL above
Start Year 2017
 
Description collaboration with Dr.Chantal Valeriani 
Organisation Complutense University of Madrid
Country Spain 
Sector Academic/University 
PI Contribution We have collaborated with Dr Valeriani and her team on the behaviour of different water models in simulations of aquaporins. We contributed expertise in water models and simulations of nanopores. This has resulted in a joint publication in J Chem Phys.
Collaborator Contribution Dr. Valeriani's post doc Dr Miguel Angel Gonzalez visited Oxford for a few weeks and worked alongside Dr Lynch (the EPSRC postdoc on this project). We have continued the collaboration online and a paper has been published in J Chem Phys.
Impact This has resulted in a joint publication in J Chem Phys.
Start Year 2018